KR100190775B1 - 11-beta-benzaldoxime-estra-4,9-diene derivatives, preparation process thereof and pharmaceutical composition containing them - Google Patents

Abstract

11-Benzaldoxime-oestradiene derivatives of the general formula I <IMAGE> and their pharmaceutically acceptable salts, a process for their preparation and pharmaceutical compositions containing them are described. The described compounds display potent antigestagenic effects with lower glucocorticoid activity.

Description

11β-Benzaldoxime-estra-4,9-diene derivative, preparation method thereof and pharmaceutical composition containing same

The present invention relates to a novel 11β-benzaldoxime-estra-4,9-diene derivative, a preparation method thereof and a pharmaceutical composition containing the same.

11β-substituted phenyl estritriene is known. European patent specification EP 057 115 describes a process for the preparation of 11β-aryl-17α-propynyl estradio-4,9-diene, and in the Federal Republic of Germany Patent Specification DE 3 504 421, 11β- (4-form The reaction of mill phenyl) estra-4,9-dien-3-one with hydroxyamine is described. Both the 11β-formyl phenylene moiety and the 3-keto group are oxime. In addition, syn and anti isomers are formed at C-3. The effect of these compounds is not yet known.

Progesterone is secreted during menstruation, and during pregnancy is produced in large quantities in the ovary and placenta. Its control materiality does not seem clear in every way.

It is known that progesterone, along with estrogen, periodically changes the menstrual cycle and uterine mucosa during pregnancy. After ovulation, the concentration of progesterone is increased so that the uterine mucosa is suitable for implantation conditions of the fetus (blastocyst). The protection of tissues in which the fetus grows internally also depends on progesterone.

Significant changes in uterine muscle function occur during pregnancy. In the non-pregnant state, the response of the pregnant uterine muscle to hypertonic hormones and mechanical stimuli is strongly reduced or absent. At this time, progesterone must act principally at certain stages of pregnancy, for example, despite the fact that they are highly responsive even at high blood levels of progesterone just before delivery.

Very high progesterone levels are also reflected by other typical processes during pregnancy. An example of this is the composition of the mammary gland until the day of delivery and obstruction of the cervix.

Progesterone tightly regulates the ovulation process. When a large amount of progesterone is administered, it is known to have ovulation inhibitory properties. This property is due to the inhibition of pituitary gonadotropin secretion which is essential for follicle maturation and its ovulation. On the other hand, however, mature follicles secrete relatively small amounts of progesterone, acting as active ingredients for ovulation preparation and induction. In this respect, the mechanism of the pituitary gland (temporary, so-called positive feedback of progesterone for gonadotropin secretion) appears to be of considerable importance. Loutradie, D .; Human Reproduction 6 , 1991, 1238-1240.

The apparent action of progesterone in mature follicles and corpus luteum is not well analyzed. In conclusion, it can be assumed that both the stimulatory and inhibitory effects on the endocrine function of the follicle and corpus luteum are present.

In addition, progesterone and progesterone receptors are considered to be of great importance for pathophysiological processes. Progesterone receptors have been found not only in endometritis lesions but also in uterine cancer, breast cancer and CNS (meningioma). The role of these receptors in relation to the growth behavior of these etiologically related tissues is not necessarily dependent on the concentration of progesterone in the blood. RU 486 = Mifepristone (EP No. 0057 115) and ZK 98299 = Materials characterized by progesterone antagonists such as Onapristone tend to cause a wide range of action changes, even if blood progesterone concentrations are negligible. In this respect, the modification of the transcriptional effect of progesterone receptors not filled with progesterone seems to be crucial (Chwalisz, K. et al., Endocrinology, 129 , 317-322, 1991).

The effects of progesterone on reproductive and other tissues are brought about by interaction with progesterone receptors. In cells, progesterone binds to its receptor with high affinity. This causes changes in receptor proteins: structural changes, dimerization of two receptor units to form one complex, and exposure of the DNA binding site of the receptor by degrading the protein (HSP 90). Eventually, transcription of certain genes is regulated. See Gronemeyer, H. et al., J. Steroid Biochem. Molec. Biol. 41, 3-8, 1992].

The effects of progesterone or progesterone antagonists do not depend only on their blood concentration. The concentration of intracellular receptors is also strongly regulated. Estrogens promote the synthesis of progesterone receptors in most tissues. Progesterone inhibits estrogen receptor and its receptor synthesis. It is speculated that the interaction between estrogen and gestagen may explain why the gestagen and antigestagen can affect estrogen dependent processes without being bound by the estrogen receptor. This relationship is, of course, of considerable importance for the therapeutic application of antigestagens. These substances have a direct effect on the female reproductive process, such as prevention of post-ovulation implantation, increased uterine responsiveness to prostaglandins and oxytocins during subsequent pregnancy, or on metherin insertion and cervical softening (maturation). Suitable for

Antigestagens suppress ovulation in the premature birth of various attracted species. The mechanism of this effect is not yet clear. Among the hypotheses discussed are the hypothesis of gonadotropin secretion and the ovarian mechanism hypothesis, which is based on the interference of para- and autocrinic functions of ovarian progesterone.

Antigestagens can modulate or attenuate the effects of estrogen even though most of them have no estrogen receptor substitution at the cytoplasmic concentration and cause increased estergen receptor concentrations. Similar effects on endometritis lesions or cancerous tissues with estrogen and progesterone receptors will have a desirable effect on pathological symptoms. Particular advantages associated with having a desirable effect on pathological symptoms, such as endometritis, can be obtained when suppressed ovulation supplements the inhibitory effect of antigestagen action in tissues. The stimulatory effect on the hormonal products of the ovaries and their pathologically modified tissues will also be reduced by inhibiting ovulation. In severe cases of endometritis, it may be desirable to suppress ovulation so that the tissues of the reproductive organs to be constantly reconstituted are in a reversible rest state.

Methods related to contraception have been discussed in which antigestagen therapy inhibits ovulation and subsequent gestational therapy induces secretion of the endometrium. Treatment and no treatment of antigestagens and gestagens over several days results in a 28-day cycle with regular withdrawal bleeding (Baulieu, EE, Advances in Contraception 7 , 345-51, 1991).

Antigestogens may have different hormone and antihormonal properties. Antiglucocorticoid properties are suitable for certain treatments. They are undesirable for therapeutic applications whose main purpose is progesterone receptor inhibition, which, when applied at the dosages required for these treatments, has undesirable side effects, preventing the application of therapeutically sensitive dosages or stopping treatment. Can be. Partial / reduced or complete reduction in glucocorticoid properties is a critical prerequisite for treatment with antigestagens, especially for symptoms requiring weeks or months of treatment.

It is an object of the present invention to provide novel 11β-benzaldoxime-estra-4,9-diene derivatives of the general formula (I) and pharmaceutically acceptable salts thereof, as well as methods of making them.

In the above formula,

Z is -CO-CH ₃ , -CO-OC ₂ H ₅ , -CO-NH-phenyl, -CO-NH-C ₂ H ₅ , -CO-C ₂ H ₅ , -CH ₃ , or CO-phenyl .

Another object of the present invention is to provide a pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof.

Preferred compounds according to the invention are as follows:

11β- [4- (acetoxyiminomethyl) phenyl] -17β-methoxy-17α-methoxymethyl-estra-4,9-dien-3-one,

11β- {4-[(ethoxycarbonyl) oxyiminomethyl] phenyl} -17β-methoxy-17α-methoxymethyl-estra-4,9-dien-3-one,

11β- {4-[(ethylaminocarbonyl) oxyiminomethyl] phenyl} -17β-methoxy-17α-methoxymethyl-estra-4,9-dien-3-one,

17β-methoxy-17α-methoxymethyl-11β- {4-[(phenylaminocarbonyl) oxyiminomethyl] phenyl} -estra-4,9-dien-3-one,

11β- [4- (propionyloxyiminomethyl) phenyl] -17β-methoxy-17α-methoxymethyl-estra-4,9-dien-3-one,

11β- [4- (methyloxyiminomethyl) phenyl] -17β-methoxy-17α-methoxymethyl-estra-4,9-dien-3-one and

11β- [4- (benzoyloxyiminomethyl) phenyl] -17β-methoxy-17α-methoxymethyl-estra-4,9-dien-3-one.

The present invention is also characterized by esterifying or etherifying a compound of formula (II) and chlorinating the resulting compound, if necessary, to prepare a compound of formula (I) and a pharmaceutically acceptable salt thereof It is about how to.

The preparation of compounds of general formula (I) by esterification, etherification or urethane formation is generally carried out using acylating agents such as acid anhydrides or acid chlorides in the presence of a base, preferably pyridine; Etherification process using methyl iodide in the presence of a base, preferably potassium tert-butanolate, or diazomethane in methanol; It can be carried out by urethane formation by reacting with alkyl or aryl isocyanates in an inert solvent, preferably toluene, or by reacting carbamoylchloride in the presence of a base, preferably triethylamine.

The parent compound of formula (II) is prepared from 5α, 10α-epoxide of formula (III).

[Reference: Bull. Soc. chim, France (1970), 2548.

The phenyl moiety is in the 11β position by the Cu (I) salt catalyzed Grignard reaction with p-bromobenzaldehyde ketal, preferably p-bromobenzaldehyde dimethylketal, at 0 to 30 ° C. (Tetrahedron Letters 1979, 2051). The Δ9 (10), 5α hydroxy structure of the following structural formula (IV) is formed at the same time.

The -CH ₂ -O-CH ₃ group reacts with trimethyl sulfonium iodide and potassium tert-butanolate in dimethyl sulfoxide [see: et al .; J. prakt, Chem. 314, 667 (1972); Arzneim. Forsch. 30, 401 (1973), followed by ring opening with alcoholate [Ponsold et al .; Z. Chem. 11, 106 (1971), through the spiroepoxide of the following formula (V) is introduced at position 17 in a generally known manner.

The resulting 17α-CH ₂ -O-CH ₃ compound of formula (VI) is preferably acid hydrolyzed with toluene-p-sulfonic acid in acetone to decompose their respective aldehydes (see Teutsch et al. DE 2801416), or etherification of free hydroxyl groups with alkylhalides in the presence of potassium tert-butanolate, followed by conversion to 5α, 17β diethers (see Kasch et al. DD 290 893). Next, they can then be converted to their respective aldehydes by acid hydrolysis with toluene-p-sulfonic acid, preferably in acetone, and the aldehyde obtained therefrom is reacted with hydroxylamine to give structural formula (II) Is converted to a compound of.

The resulting compound of formula (I) according to the invention is converted, if necessary, into acid addition salts, preferably salts of physiologically acceptable acids. Examples of physiologically acceptable conventional inorganic and organic acids are hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, oxalic acid, maleic acid, fumaric acid, lactic acid, tartaric acid, malic acid, citric acid, salicylic acid, adipic acid and benzoic acid. Other acids that can be used are described in the literature. See, eg, Fortschritte der Arzneimittel forschung, Vol. 10, pp. 224-225, Birkhauser Verlag, Basel and Stuttgart, 1966 and Journal of Pharmaceutical Sciences, Vol. 66, pp. 1-5 (1977).].

Acid addition salts are generally known methods and are usually prepared by free base or a solution thereof in an organic solvent such as a lower alcohol (eg methanol, ethanol, n-propanol or isopropanol) or a lower ketone (eg acetone, methyl ethyl). Ketone or methyl isobutyl ketone) or obtained by mixing with each acid or a solution thereof in an ether such as diethyl ether, tetrahydrofuran or dioxane. Compositions of these solvents can be used to enhance crystallization. In addition, a physiologically acceptable anhydrous solution of the acid addition salt of the compound according to general formula (I) may be prepared in the form of an anhydrous acidic solution.

Acid addition salts of compounds of general formula (I) can be converted to the free base by generally known methods, for example using alkalis or ion exchangers. Other salts can be obtained by reacting this free base with an inorganic or organic acid, in particular with an acid suitable for pharmaceutically acceptable salt formation. Salts such as the above, and other salts of the novel compounds, such as picrates, can be used to purify the free base, which salts are converted to salts and the base is released from the salt again.

Another object of the present invention is a pharmaceutical for oral, rectal, subcutaneous, intravenous or intramuscular administration which contains, as an active ingredient, a compound of formula (I) or an acid addition salt thereof as well as a conventional substrate and diluent.

Pharmaceuticals of the present invention are prepared in a known manner using conventional solid or liquid substrates or diluents and conventional auxiliaries used in the pharmaceutical industry so that suitable dosages will depend on the desired mode of administration. Preferred formulations are in a form suitable for oral administration, for example in the form of tablets, film tablets, dragees, capsules, pills, powders, solutions, suspensions or accumulators.

In addition, parenteral formulations such as injection solutions are also contemplated. Suppositories are another form of application.

Tablets may contain, for example, the active ingredient with known auxiliaries such as inert diluents (eg dextrose, sugars, sorbitol, manganese, polyvinyl pyrrolidone), blowing agents (eg corn starch or alginic acid) , Binders (e.g. starch or gelatin), lubricants (e.g. magnesium stearate or talc) and / or substances which provide an accumulation effect (e.g. carboxyl polymethylene, carboxymethyl cellulose, cellulose acetate phthalate or polyvinyl acetate) Can be obtained by mixing.

Dragees are coated by cores prepared in a similar manner to tablet preparation using reagents commonly applied to dragee coatings, for example, polyvinylpyrrolidone or shellac, gum arabic, talc, titanium dioxide or sugars. It can manufacture. Dragee coatings may also consist of several layers within which the adjuvant mentioned in the paragraph above for tablets may be used.

Solutions or suspensions containing the active agents of the present invention may further contain flavor enhancing substances such as saccharin, cyclates or sugars or aromatic substances such as vanillin or orange extracts. They may also contain suspension support aids such as sodium carboxymethyl cellulose or preservatives such as p-hydroxybenzoate. Capsules containing the active ingredient can be prepared, for example, by mixing the active ingredient with an inert substrate (eg lactose or sorbitol) and encapsulating the mixture in gelatin capsules.

Suitable suppositories can be prepared by mixing the active ingredient with a suitable substrate, such as natural lipids or polyethylene glycols and derivatives thereof.

The 11β-benzaldoxime-estra-4,9-diene of the present invention has a higher in vivo activity potential when compared to RU 486 (see Table 2) and significantly reduced antiglucocorticoid activity [this is a glucocorticoid receptor Has been demonstrated to have reduced binding to (see Table 1).

TABLE 1

Receptor binding of selected materials described in Examples 1 and 2

The combined properties of the antigestagen agents according to the invention promise good inhibition of progesterone and at the same time reduce glucocorticoid activity. This advantage is particularly suitable for symptoms requiring good tolerance due to the continuing treatment. During the menstrual cycle, uterine compression is critically affected by circulating estrogens. The reduction in uterine compression reflects this suppression of estrogenous action. Inhibition of uterine compression during the menstrual cycle, measured in guinea pigs, is superior to RU 486, which exhibits strogen characteristics in the (direct) term of the compounds according to the invention. Each effect has a particularly desirable effect on pathologically modified tissues (endometritis lesions, myomas, breast and genital cancers, benign prostatic hypertrophy), in which the steroids stimulate growth.

TABLE 2

0.2 ml / animal in RU 486 and J 914 (Example 1) and J 900 (Example 2) (dosage, benzylbenzoate / castor oil [1 + 4v / v] in rats after subcutaneous administration on days 5-7 / Day] 's early miscarriage effect

The following examples illustrate the invention.

(Example 1)

180 mg of 11β- [4- (hydroxyiminomethyl) phenyl] -17β-methoxy-17α-methoxymethyl-estra-4,9-dien-3-one acetyl in 5 ml of acetic anhydride / pyridine (1: 1) Make up. After adding water, the batch is extracted three times with acetic acid ester. The organic phase is washed with dilute hydrochloric acid and water, dried over sodium sulfate, then evaporated and concentrated under reduced pressure. 172 mg of crude product are obtained, which are purified by preparative thin layer chromatography using silica gel PF _{245 + 366} and a toluene / acetone solvent system at 4: 1 concentration.

Yield: 115 mg of 11β- [4- (acetoxyiminomethyl) phenyl] -17β-methoxy-17α-methoxymethyl-estra-4,9-dien-3-one. The product is crystallized from acetic acid ester.

Melting point: 115 to 120 ° C. (acetic acid ester)

α _D = + 218 ° (CHCl ₃ )

IR spectrum in KBr (cm ⁻¹ ): 1754 (OAc);

1654 (C═C—C═C—C═O); 1602 (phenyl)

UV spectrum in MeOH: λ _max = 271 nm ε = 28 157

λ _max = 297 nm ε = 26 369

¹ H-NMR spectrum [δ, ppm] in CDCl ₃ : 0.511 (s, 3H, H-18); 2.227 (s, 3H, OCOCH ₃ ); 3.247 (s, 3H, 17β-OCH ₃ ); 3.408 (s, 3H, 17α-CH ₂ OCH ₃ ); 3.386, 3.431, 3.544, 3.580 (m, 2H, CH ₂ OCH ₃ ); 4.399 (d, 1H, J = 7.2 μs, H-11α); 5,785 (s, 1 H, H-4); 7.242, 7.266, 7.618, 7.647 (m, 4H, AA'BB 'system of aromatic protons); 8.315 (s, 1H, CH = NOAc)

MS m / e: 446 C ₂₈ H ₃₂ NO ₄ M ⁺ -CH ₂ OCH ⁺ 3

(Example 2)

210 mg of 11β- [4- (hydroxyiminomethyl) phenyl] -17β-methoxy-17α-methoxymethyl-estra-4,9-dien-3-one in 5 ml of pyridine with 0.3 ml of chloroethyl formate molar cooled Drop by. White precipitate is formed. After 30 minutes, the batch is added with water to form a solution with a white precipitate, which is filtered off with suction and washed with water. Yield after drying: 133 mg. The aqueous phase is extracted with chloroform, washed with dilute hydrochloric acid and water, then dried and concentrated by evaporation under reduced pressure. Yield: 66 mg. The two solids are combined and purified by preparative thin layer chromatography using a silica gel PF _{245 + 366} and a 4: 1 toluene / acetone solvent system.

Yield: 150 mg of 11β- [4- (ethoxycarbonyloxyiminomethyl) phenyl] -17β-methoxy-17α-methoxymethyl-estra-4,9-dien-3-one, which is from acetol / hexane Recrystallize.

Melting Point: 137-148 ° C

α _D = + 204 ° (CHCl ₃ )

UV spectrum in MeOH: λ _max = 270 nm ε = 27 094

λ _max = 297 nm ε = 25 604

¹ H-NMR spectrum [δ, ppm] in CDCl ₃ : 0.507 (s, 3H, H-18); 1.383 (t, 3H, J = 7.0 Hz, OCH ₂ CH ₃ ); 3.246 (s, 3H, 17β-OCH ₃ ); 3.410 (s, 3H, 17α-CH ₂ OCH ₃ ); 3.39-3.56 (m, 2H, CH ₂ OCH ₃ ); 4.35 (d, 1H, J = 7.0 Hz, H-11α); 5.784 (s, 1 H, H-4); 7.23, 7.26, 7.61, 7.64 (m, 4H, AA'BB 'system of aromatic protons); 8.303 (s, 1H, CH = NR)

MS m / e: 431.24701 C ₂₈ H ₃₂ NO ₃ M ⁺ -C ₂ H ₅ OCOOH

(Example 3)

190 mg of 11β- [4- (hydroxyiminomethyl) phenyl] -17β-methoxy-17α-methoxymethyl-estra-4,9-dien-3-one are suspended in 10 ml toluene. Then 0.5 ml of phenyl isocyanate and 1 ml of triethylamine are added. The batch is shaken for 3 hours at room temperature and refluxed for 2 hours. The white precipitate is suction filtered and the solvent is concentrated by evaporation under reduced pressure. Thus, 310 mg of a light brown solid is obtained, which is purified by preparative thin layer chromatography using silica gel PF _{245 + 366} and a 9: 1 concentration toluene / acetone solvent system.

65 mg of 17β-methoxy-17α-methoxymethyl-11β- {4-[(phenyl-amino-carbonyl) oxyiminomethyl)] phenyl} -estra-4,9-dien-3-one are isolated.

Melting point: 241 to 246 ° C. (acetone)

α _D = + 178 ° (CHCl ₃ )

UV spectrum in MeOH: λ _max = 238 nm ε = 29 444

λ _max = 300 nm ε = 29 649

¹ H-NMR spectrum [δ, ppm] in CDCl ₃ : 0.474 (s, 3H, H-18); 3.245 (s, 3H, 17β-OCH ₃ ); 3.405 (s, 3H, 17α-CH ₂ OCH ₃ ); 3.406-3.545 (m, 2H, ABX system, 17α-CH ₂ OCH ₃ ); 4.413 (d, 1H, J = 6.8 Hz, H-11α); 5,797 (s, 1 H, H-4); 7.264 (m, 5H, aromatic), 7.272, 7.293, 7.548, 7.575 (m, 4H, AA'BB 'system of aromatic protons); 8 0 (s, 1H, CH = N-)

MS m / e: 431.24249 C ₂₈ H ₃₃ NO ₃ M ⁺ -C ₆ H ₅ CNO + H ₂ O

(Example 4)

708 mg of 11β- [4- (hydroxyiminomethyl) phenyl] -17β-methoxy-17α-methoxymethyl-estra-4,9-dien-3-one are dissolved in 15 ml of toluene. Then 1.5 ml of ethyl isocyanate and 3 ml of triethylamine are added. The batch is shaken for 6 hours at room temperature and left overnight. 20 ml of aqueous ammonium solution is then added to separate the phases, extracted with toluene, washed in water, aqueous ammonium solution and water, dried over sodium sulfate and then concentrated by evaporation under reduced pressure. Thus, 800 mg of a pale yellow solid was obtained, which was purified by preparative thin layer chromatography using silica gel PF _{254 + 366} and a 9: 1 concentration toluene / acetone solvent system.

610 mg of 11β- {4-[(ethylaminocarbonyl) oxyiminomethyl)] phenyl} -17β-methoxy-17α-methoxymethyl-estra-4,9-dien-3-one are isolated.

Melting point: 142-147 ° C. photolysis (ether / acetone / hexane)

¹ H-NMR spectrum [δ, ppm] in CDCl ₃ : 0.522 (s, 3H, H-18); 1.241 (t, 3H, J = 7.5 s, NHCH ₂ CH ₃ ); 3.253 (s, 3H, 17β-OCH ₃ ); 3.415 (s, 3H, 17α-CH ₂ OCH ₃ ); 3.366-3.574 (m, 4H, ABX system, 17α-CH ₂ OCH ₃ , NHCH ₂ CH ₃ ); 4.410 (d, 1H, J = 7.2 μs, H-11α); 5,790 (s, 1 H, H-4); 6.238 (m, 1H, NHCO), 7.258, 7.286, 7.561, 7.589 (m, 4H, AA'BB 'system of aromatic protons); 8.294 (s, 1H, CH = N-)

(Example 5)

500 mg of 11β- [4- (hydroxyiminomethyl) phenyl] -17β-methoxy-17α-methoxymethyl-estra-4,9-dien-3-one propionic anhydride / pyridin 1: 1 (v: v) Stirred and exposed to inert gas for 2.5 hours in 4 ml. The mixture is poured into ice water and the viscous material is extracted with chloroform. The organic phase is washed with dilute hydrochloric acid and water, dried over sodium sulfate and then concentrated by evaporation under reduced pressure. The pale yellow foam is purified by chromatography and recrystallized from acetic acid ester.

Yield: 306 mg of 11β- [4- (propionyloxyiminomethyl) phenyl] -17β-methoxy-17α-methoxymethyl-estra-4,9-dien-3-one.

Melting point: 110-114 ° C (acetic acid ester)

¹ H-NMR spectrum [δ, ppm] in CDCl ₃ : 0.515 (s, 3H, H-18); 1.241 (t, 3H, J = 7.6 kPa, OCOCH ₂ CH ₃ ); 3.253 (s, 3H, 17β-OCH ₃ ); 3.415 (s, 3H, 17α-CH ₂ OCH ₃ ); 3.4-3.6 (m, 2H, ABX system, 17α-CH ₂ OCH ₃ ); 4.128 (d, 1H, J = 7.2 μs, H-11α); 5.790 (s, 1 H, H-4); 7.244, 7.271, 7.627, 7.655 (m, 4H, AA'BB 'system of aromatic protons); 8.322 (s, 1H, CH = N-)

(Example 6)

To 170 mg of 11β- [4- (hydroxyiminomethyl) phenyl] -17β-methoxy-17α-methoxymethyl-estra-4,9-dien-3-one the mixture of ethereal diazomethane solution with ice cooling Add until it turns pale yellow. The batch is stirred at 5 ° C. for 2 hours and dilute sodium hydroxide solution is added. The mixture is then extracted with ether, washed with neutral and dried over sodium sulfate. The organic phase is evaporated under reduced pressure. The yellow resin is purified by preparative thin layer chromatography using silica gel 60 PF _{254 + 366} and a 4: 1 toluene / acetone solvent system.

Yield: 110 mg of 11β- [4- (methoxyiminomethyl) phenyl] -17β-methoxy-17α-methoxymethyl-estra-4,9-dien-3-one in the form of a colorless thin film.

Melting point: 83-89 ° C

α _D = + 197 ° (CHCl ₃ )

IR spectrum (cm ⁻¹ ) in CHCl ₃ : 1700 (C = NOCH ₃ ); 1649 (C = CC = CC = O); 1590 (aromatic)

UV spectrum in MeOH: λ _max = 275 nm ε = 23 098

λ _max = 300 nm ε = 22 872

¹ H-NMR spectrum [δ, ppm] in CDCl ₃ : 0.529 (s, 3H, H-18); 3.247 (s, 3H, 17β-OCH ₃ ); 3.408 (s, 3H, 17α-CH ₂ OCH ₃ ); 3.39-3.598 (m, 2H, ABX system, 17α-CH ₂ OCH ₃ ); 4.381 (d, 1H, J = 7.5 μs, H-11α); 5.773 (s, 1 H, H-4); 7.173, 7.201, 7.463, 7.491 (m, 4H, AA'BB 'system of aromatic protons); 8.023 (s, 1 H, CH phenyl)

(Example 7)

A filtered mixture of 2 ml of benzoyl chloride and 3 ml of pyridine is added to 500 mg of 11β- [4- (hydroxyiminomethyl) phenyl] -17β-methoxy-17α-methoxymethyl-estra-4,9-dien-3-one. . After 2 hours, the mixture is stirred into 150 ml of cold water. Steroids precipitate as viscous substances. 5 ml of hydrochloric acid are added and the mixture is dissolved in acetic acid ester. The phases are separated and the organic phase is washed with aqueous bicarbonate solution and water, then dried over sodium sulfate, filtered and then evaporated under reduced pressure. Yellow oil (1.57 g) is chromatographed using 40 g silica gel 60 using a toluene / acetic acid ester gradient to liberate from the nonpolar product. The main fraction (0.7 g) is purified by preparative thin layer chromatography using silica gel 60 PF _{254 + 366} and a chloroform / acetone solvent system. 410 mg of colorless foam are obtained and recrystallized from methanol.

Yield: 263 mg of 11β- [4- (benzoyloxyiminomethyl) phenyl] -17β-methoxy-17α-methoxymethyl-estra-4,9-dien-3-one as a colorless foam.

Melting Point: 115 to 122 ° C. (Methanol)

α _D = + 216 ° (CHCl ₃ )

UV spectrum in MeOH: λ _max = 279 nm ε = 33 720

λ _max = 299 nm ε = 30 120

¹ H-NMR spectrum [δ, ppm] in CDCl ₃ : 0.527 (s, 3H, H-18); 3.253 (s, 3H, 17β-OCH ₃ ); 3.415 (s, 3H, 17α-CH ₂ OCH ₃ ); 3.403-3.598 (m, 2H, ABX system, 17α-CH ₂ OCH ₃ ); 4.416 (d, 1H, J = 7.2 Hz, H-11α); 5,792 (s, 1 H, H-4); 7.299-7.615 (m, 5H, aromatic protons, COphenyl); 7.701, 7.729, 8.111, 8.140 (m, 4H, AA'BB 'system of aromatic protons); 8.520 (s, 1 H, CH phenyl)

(Example 8)

Binding affinity measurement to receptors

Receptor binding affinity for receptors in the cytosol of animal target organs is determined by competitive binding of the specific binding ³ H labeling hormone (tracer) with the compound to be tested. The following culture conditions were chosen in an attempt to obtain receptor saturation and equilibrium reactions:

Glucocorticoid Receptor: Thymic cytosol of adrenal exterminated rats, maintaining thymus at −30 ° C., buffer: TED. Tracer: ³ H-dexamethazone, 20 nM: Reference Substance: dexamethasone.

After 18 hours of incubation at 0-4 ° C., the binding and free steroids are mixed in activated carbon / dextran (1% / 0.1%), centrifuged and separated by measuring bound ³ H activity in the supernatant. .

IC ₅₀ for the compound to be tested and the reference material are determined from measurements at a series of concentrations. The quotient of the two values (x 100%) is the relative molar bond affinity.

(Example 9)

Early Pregnancy Suppression in Rats

Rat females are mated in estrus. If semen is then found in vaginal smear, this time is calculated as day 1 (= d1) of pregnancy. Treat with test substance or vehicle on days 5-7 and inspect on day 9. 0.2 ml of test substance in vehicle (benzoyl benzoate / castor oil 1 + 4) is injected subcutaneously. Complete pregnancy inhibition rates of various groups are shown in Table 1. It was found that the anti-imaging performance for J 917 and J 900 was superior to RU 486.

Claims (4)

11β-Benzaldoxime-estra-4,9-diene derivative of formula (I) and a pharmaceutically acceptable salt thereof. In the above formula, Z is -CO-CH ₃ , -CO-OC ₂ H ₅ , -CO-NH-phenyl, -CO-NH-C ₂ H ₅ , -CO-C ₂ H ₅ , -CH ₃ or CO-phenyl. The method of claim 1, 11β- [4- (acetoxyiminomethyl) phenyl] -17β-methoxy-17α-methoxymethyl-estra-4,9-dien-3-one and 11β- {4-[(ethoxycarbonyl) oxyiminomethyl] phenyl} -17β-methoxy-17α-methoxymethyl-estra-4,9-dien-3-one and 11β- {4-[(ethylaminocarbonyl) oxyiminomethyl] phenyl} -17β-methoxy-17α-methoxymethyl-estra-4,9-dien-3-one, 17β-methoxy-17α-methoxymethyl-11β- {4-[(phenylaminocarbonyl) oxyiminomethyl] phenyl} -estra-4,9-dien-3-one, 11β- [4- (propionyloxyiminomethyl) phenyl] -17β-methoxy-17α-methoxymethyl-estra-4,9-dien-3-one, 11β- [4- (methyloxyiminomethyl) phenyl] -17β-methoxy-17α-methoxymethyl-estra-4,9-dien-3-one and 11β- [4- (benzoyloxyiminomethyl) phenyl] -17β-methoxy-17α-methoxymethyl-estra-4,9-dien-3-one. A process for preparing a compound of formula (I) according to claim 1 and a pharmaceutically acceptable salt thereof, characterized in that the compound of formula (II) is esterified or etherified in a generally known manner. In the above formula, Z is -CO-CH ₃ , -CO-OC ₂ H ₅ , -CO-NH-phenyl, -CO-NH-C ₂ H ₅ , -CO-C ₂ H ₅ , -CH ₃ or CO-phenyl. (Correction) A pharmaceutical composition useful as an antigestagen agent, comprising at least one compound according to claim 1 or 2 as an active ingredient.